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Original Research |
1 Departments of Radiology, Pathology, and Surgery, Kitasato University School
of Medicine and Kitasato University Hospital, Sagamihara, Kanagawa,
Japan.
2 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School,
Boston, MA.
3 Centre for Clinical Spectroscopy, Department of Radiology, Brigham and Women's
Hospital and Harvard Medical School, Boston, MA.
4 Present address: Department of Radiology, Kitasato University School of
Medicine, 1-15-1, Kitasato, Sagamihara, Kanagawa, 228-8555 Japan.
Received August 15, 2008;
accepted after revision January 9, 2009.
FOR YOUR INFORMATION
Abstract
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SUBJECTS AND METHODS. Two hundred seventy-six patients with 277 lesions, including 15 mucinous carcinomas (13 pure type, two mixed type), 204 other malignant tumors, and 58 benign lesions, were examined with 1.5-T MRI at b values of 0 and 1,500 s/mm2. The correlations between cellularity and ADC, homogeneity of signal intensity on diffusion-weighted images, and histopathologic findings were analyzed. The difference was statistically significant (p < 0.05).
RESULTS. The mean ADC of mucinous carcinoma (1.8 ± 0.4
x 10-3 mm2/s) was statistically higher than that
of benign lesions (1.3± 0.3 x 10-3 mm2/s)
and other malignant tumors (0.9 ± 0.2 x 10-3
mm2/s) (p < 0.001). The ADC of pure type mucinous
carcinoma (1.8 ± 0.3 x 10-3 mm2/s) was
higher than that of mixed type mucinous carcinoma (1.2 ± 0.2 x
10-3 mm2/s) (p < 0.001) and other histologic
types (p > 0.05). The correlation between mean cellularity and the
ADC of mucinous carcinoma was significant (
s = -0.754;
p = 0.001). The homogeneity of signal intensity on diffusion-weighted
images correlated with the homogeneity of histologic structures of mucinous
carcinoma (p < 0.001; 
= 0.826).
CONCLUSION. Mucinous carcinoma can be clearly differentiated from other breast tumors on the basis of ADC. The low signal intensity of mucinous carcinoma on diffusion-weighted images appears to reflect the presence of mucin and low cellularity. High signal intensity on diffusion-weighted images may reflect the presence of fibrovascular bundles, increased cell density, or a combination of these features.
Keywords: ADC valve • breast • diffusion-weighted imaging • MRI • mucinous carcinoma of the breast
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Mucinous carcinoma of the breast is a relatively rare tumor that accounts for 1-7% of all cases of breast cancer. It is defined by a histologically distinctive pattern characterized by proliferation of clusters of generally uniform round cells floating in large amounts of extracellular mucus, as described in the World Health Organization international histologic classification of tumors [5]. There are two types of mucinous carcinoma. In the pure type, all of the tumor cells are completely surrounded by mucin, and the tumor does not have any invasive ductal components. In the mixed type, invasive ductal carcinoma is present but not embedded in extracellular mucin. Pathologic specimens of mucinous carcinoma of the breast vary in the amount of mucin and cells and are described as having the hypercellular and hypocellular properties of mucinous carcinoma of the breast [5].
We hypothesized that the ADC and DWI signal intensity of mucinous carcinoma of the breast vary depending on amount of mucin, cellularity, and fibrous stroma. This hypothesis was based on results of previous studies of tumors of various organs, including the brain, pancreas, and other soft tissues, that pointed to the influence of cellularity, fibrosis, and mucous matrix on ADC [6-9]. The aim of this study was to compare the ADC of mucinous carcinoma of the breast with the ADCs of other breast tumors. We also examined the correlation between signal intensity on diffusion-weighted images and the histopathologic features of mucinous carcinoma of the breast.
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MRI
Routine breast MRI was performed with a 1.5-T MRI system (HDx, GE
Healthcare) and a dedicated eight-channel breast-array coil on patients in the
prone position. After the positioning acquisition, DWI of both breasts was
performed in the axial plane with the single-shot echo-planar imaging sequence
to reduce motion artifacts (TR/TE, 9,500/89; section thickness, 4.0 mm;
interslice gap, 0 mm; number of signals averaged, 8; field of view, 320
mm2; matrix size, 160 x 224; no parallel imaging because of
the possibility of unfold failure and lower signal-to-noise ratio). Data were
collected at b values of 0 and 1,500 s/mm2. The b value of 1,500
s/mm2 was used to minimize the T2-weighted shine-through effect and
to suppress the signal from normal breast parenchyma
[10]. In addition, a
frequency-selective radiofrequency pulse was used before the pulse sequence to
suppress the strong signal from lipids, reducing chemical shift artifacts. The
acquisition time for DWI was 5 minutes.
After DWI, unilateral examination of the index breast consisted of a sagittal fast spin-echo T2-weighted sequence with fat suppression (4,000/90; section thickness, 5 mm; interslice gap, 2 mm; number of signals averaged, 2; field of view, 200 mm; matrix size, 288 x 219) and a sagittal 3D T1-weighted fast gradient-echo sequence (16.3/2.1; flip angle, 15°; section thickness, 2 mm; number of signals averaged, 1.5; field of view, 200 mm; matrix size, 288 x 192) with chemical shift selective suppression technique for active suppression of the fat signal. For the dynamic contrast-enhanced portion of the study, a bolus injection of 0.10 mmol/kg of body weight of gadopentetate dimeglumine (Magnevist, Bayer HealthCare) was administered through the right antecubital vein with an automatic injector (Sonic Shot 50, Nemoto Kyorindo). The injection rate was 2 mL/s, and the contrast agent was followed by a 20-mL saline flush. Acquisitions were performed before and 90 seconds (early phase) and 300 seconds (delayed phase) after contrast injection. An ADC map was generated on a workstation (Advantage Windows 4.1, GE Healthcare) from diffusion-weighted images with b values of 0 and 1,500 s/mm2.
Assessment of ADC, Diffusion-Weighted Images, and Corresponding Histopathologic Structures
Measurement of ADC of all tumors—Calculation of the ADC of
all tumors was by one radiologist with 6 years of experience in breast
imaging, including MRI. This investigator was not aware of the histopathologic
diagnosis in any case. The location of tumors on the diffusion-weighted images
and ADC maps was determined on fat-suppressed T2-weighted and
contrast-enhanced T1-weighted images. The region of interest covering the
whole tumor was placed on the ADC map, and the ADC was recorded. If the
presence of hemorrhage or necrosis was suspected on the basis of the findings
on the unenhanced T1- and T2-weighted images, the region of interest did not
include that area [11].
Regions of interest were placed inside the tumor on all slices that displayed
the tumor and were averaged. Calculation of the ADC of each tumor was
repeated, and the values were averaged. We disregarded satellite lesions
coexisting with main tumors. The mean ADCs of mucinous carcinomas, other
malignant breast tumors, and benign breast tumors were compared.
Pathologic analysis of mucinous carcinoma— Each resected specimen of mucinous carcinoma was obtained with four sutures of various lengths with the axilla, nipple side, cranial margin, and caudal margin for orientation. Surgical specimens were cut into 5-mm slices, fixed in 10% neutral-buffered formalin, and processed for histologic examination. The specimens were stained with H and E and evaluated by a pathologist expert in breast pathology. Mucinous carcinomas of the two subtypes, pure and mixed, were examined.
The cellularity of mucinous carcinoma was analyzed according to the methods of previous studies [1] with National Institutes of Health Image J 1.40g software with a Windows operating system. The original magnification of the specimens was x200. A pathologist analyzed five sample views randomly chosen from the specimens for cellularity values. The mean cellularity of each tumor was calculated by averaging of these five values. The correlation between the mean cellularity value and ADC was statistically analyzed.
Comparison between DWI and histopathologic findings of mucinous carcinoma—We matched the tumor on the diffusion-weighted images and the specimens by referring to the pathologic diagram that displayed each orientation of each specimen in the resected breast tissue. On the basis of previous reports [1, 6, 9, 12] of the correlation between ADC and the presence of mucus, degree of cellularity, and the degree of fibrosis in other organs, we hypothesized that the pattern of signal intensity on diffusion-weighted images would reflect the histopathologic structure of mucinous carcinoma. In this study, signal intensity on diffusion-weighted images was considered inversely proportional to ADC because the effect of T2-weighted shine-through was considered to be at a minimum owing to the b value of 1,500 s/mm2 [13]. Therefore, we hypothesized that the specimens with high DWI signal intensity would correlate with high-cellularity lesions or fibrovascular tissue and the specimens with low DWI signal intensity would correlate with low-cellularity, mucin-rich lesions.
The homogeneity of the signal intensity pattern of mucinous carcinoma on diffusion-weighted images was categorized as homogeneously high signal intensity, which was higher than the signal intensity of the rib or sternum; homogeneously low signal intensity, which was lower than or equal to the signal intensity of the rib or sternum; and heterogeneous signal intensity, a composite of high and low signal intensity. Each lesion was categorized by two radiologists with more than 6 years of experience in MRI, including breast MRI. If there was a discrepancy between the two readers, they discussed the findings and made a final decision.
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The correlation between homogeneity of signal intensity on diffusion-weighted images and homogeneity of histologic structure was assessed. The lesions categorized as having heterogeneous signal intensity on diffusion-weighted images were analyzed in detail with regard to histopathologic characteristics.
Statistical Analysis
Statistical analysis was performed with JMP software (version 7.0, SAS
Institute). The mean ADCs of mucinous carcinomas, other breast malignant
tumors, and benign breast tumors were com pared by the Student's t
test. The mean ADCs of pure mucinous carcinoma and mixed mucinous carcinoma
were compared by the Mann-Whitney U test. A value of p <
0.05 was considered significant. Spearman's correlation was used to evaluate
the relation between the mean cellularity and the ADC of mucinous carcinoma. A
value of p < 0.05 was considered to indicate a statistically
significant difference. Correlation between signal intensity pattern on
diffusion-weighted images and histologic homogeneity was validated with kappa
statistics.
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s = -0.754; p
= 0.001) (Fig. 2).
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On diffusion-weighted images, mucinous carcinoma of the breast had
homogeneously high signal intensity in one case, homogeneously low signal
intensity in three patients, and heterogeneity in 11 patients
(Table 3). In the comparison of
the signal intensity pattern of mucinous carcinoma on diffusion-weighted
images and the histologic homogeneity of the specimens, the only tumor with
homogeneously high signal intensity on diffusion-weighted images exhibited
homogeneously high cellularity in the specimens (Figs.
3A,
3B, and
3C). Two of the three lesions
with homogeneously low signal intensity on diffusion-weighted images were
found to have homogeneously low cellularity and mucin-rich content (Figs.
4A,
4B, and
4C). In the third patient,
homogeneous mucin-rich content with thin fibrovascular tissue demarcating the
border of the tumor was found. Specimens of all 11 tumors with heterogeneous
signal intensity on diffusion-weighted images had a combination of low
cellularity, mucin-rich content, and high-cellularity content or a combination
of low cellularity, mucin-rich content, and fibrovascular tissue (Figs.
5A,
5B, and
5C). The correlation between
the homogeneity of the signal-intensity patterns on diffusion-weighted images
and the histologic homogeneity of the specimens was significant (p
< 0.001; = 0.826).
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Regarding the 11 tumors with heterogeneous signal intensity on diffusion-weighted images, we classified the pattern of the high-signal-intensity compartment into linear and nodular patterns to correlate these features with the histologic structure of the lesion. These 11 cases with heterogeneous signal intensity on diffusion-weighted images and the corresponding histologic structures are summarized in Table 4.
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The ADC of mucinous carcinoma also was higher than that of benign breast tumors. However, some benign breast tumors, particularly fibroadenoma and benign phyllodes tumor (Table 1), have high ADCs overlapping those of mucinous carcinoma. Myxomatous or edematous stroma, which is sometimes found in fibroadenoma and phyllodes tumor on histopathologic images, may be the cause of high ADCs [16-18]. Articles [18, 19] have described the characteristics of mucinous carcinoma on conventional MRI. They mention the similarity between fibroadenoma and pure mucinous carcinoma on T2-weighted images and contrast-enhanced T1-weighted images. The comprehensive approach of DWI, ADC calculation, and conventional MRI to increase specificity is a subject for further study.
Cysts were not included in our benign lesions. The ADCs of simple cysts can overlap those of pure mucinous carcinoma [20]. On diffusion-weighted images, the appearance of pure mucinous carcinoma, which has homogeneously low signal intensity, may be similar to the that of cysts. Complicated cysts, such as highly condensed cysts and bloody cysts, can mimic the DWI findings and ADCs of mixed mucinous carcinoma and those of other malignant tumors because they have low ADCs [21, 22]. These issues need further study.
The number of mixed mucinous carcinomas in our study was too small for reliable conclusions about ADCs, but the two mixed mucinous carcinomas had significantly lower ADCs than pure mucinous carcinoma. According to general pathologic findings [16, 17], the cellularity of mixed mucinous carcinoma tends to be greater than that of pure mucinous carcinoma. A previous study [23] showed that the proportion of extracellular mucin in mixed mucinous carcinoma was less than that of pure mucinous carcinoma. Our study also showed an inverse correlation between the cellularity of mucinous carcinoma of the breast and ADC (Fig. 2). Therefore, it seems likely that the high cellularity and lower mucin matrix of mixed mucinous carcinoma contribute to its low ADC. If the tumor is already suspected of being mucinous carcinoma at MRI that includes DWI, a lower ADC of mucinous carcinoma may indicate the tumor is mixed mucinous carcinoma.
It may not be possible to differentiate mixed and pure mucinous carcinoma with conventional MRI of the breast [24]. Mixed mucinous carcinoma has a worse prognosis and a higher incidence of axillary lymph node metastasis than does pure mucinous carcinoma [23]. Thus the DWI features and ADC of mucinous carcinoma may supply additional information for prognosis. The diagnosis of mixed mucinous carcinoma can be difficult, however, if there is no information suggesting the possibility of the presence of mucinous carcinoma. There was no significant difference between the ADC of mixed mucinous carcinoma and that of other histologic types of breast tumors except pure mucinous carcinoma. This issue needs further evaluation.
Our study showed a significant correlation between signal intensity pattern on diffusion-weighted images and histologic features. The finding of a low-signal-intensity compartment is evidence of the presence of a mucin-rich, low cellularity compartment. The study also showed that not only high cellularity but also fibrous stroma is a cause of high signal intensity on diffusion-weighted images. This correlation is consistent with the findings in several previous reports [9, 12, 25] on the inverse correlation between ADC and degree of fibrosis. The high cellularity may narrow the free space for water diffusion, and fibrous tissue works as a boundary and obstacle to the diffusibility of water molecules.
To our knowledge, this study is the first to show the possible correlation between high signal intensity on diffusion-weighted images and the presence of fibrous stroma in breast tumors. Because there appears to be a correlation between the presence of a high-signal-intensity lesion on diffusion-weighted images and its corresponding histologic structure, the morphologic features of a high-signal-intensity lesion may also represent the histologic structure. Linear high signal intensity is highly likely to be a sign of the presence of fibrous tissue, and nodular high signal intensity may be a sign of a the presence of either fibrous tissue or a high-cellularity lesion. It is not yet known whether the nature of the fibrovascular tissue on its own is a cause of high signal intensity on diffusion-weighted images. The neighboring structure, which is the mucin matrix in mucinous carcinoma, and infiltrating inflammatory cells and other factors may interact in concert with the fibrous tissue to cause high signal intensity. This issue needs further investigation.
One of the limitations of this study was the premise of the minimum T2-weighted shine-through effect at DWI with a b value of 1,500 s/mm2. T2-weighted shine-through cannot be eliminated even with a higher b value. The contrast of the signal intensity between solid lesions, mucin lesions, and water lesions is larger with a higher b value than with a lower b value, as shown in a previous study of evaluation of pancreatic cystic tumors at a b value of 1,000s/mm2 [21]. Another limitation was that the number of mixed mucinous carcinomas was too small for definitive comparison with pure mucinous carcinoma and other histologic types of breast tumors. The number of subjects with each benign tumor also was small. We need a larger number of subjects with each histologic type to reach a more reliable conclusion about comparison of ADCs between histologic types.
We did not analyze the ADC of each signal component inside the mucinous carcinomas at DWI. Some of the tumors were small, and the ADCs of the components might have been inaccurate because of the partial volume effect. Pathologic specimens were not sliced according to the slice direction of DWI. Therefore, one-to-one correspondence between components on the tumor on diffusion-weighted images and in the histologic specimens was not strictly achieved. The location and outline of each signal-intensity component and those of the expected corresponding histologic structure were matched. We used bilateral DWI and unilateral conventional T1- and T2-weighted imaging and contrast-enhanced imaging because at the time we were not satisfied with the quality of transverse bilateral breast dynamic images with volume imaging for breast assessment (Vibrant, GE Healthcare) compared with unilateral sagittal images. Therefore, we did not use bilateral imaging for dynamic studies. The quality of bilateral imaging has improved, and we are performing bilateral imaging for all sequences.
DWI may be a helpful and supportive tool for conventional MRI, especially if integrated with standard metrics for lesions detected with breast MRI, such as signal intensity on T1- and T2-weighted images, morphologic features of lesions, and contrast enhancement kinetics. We suspect that better sensitivity and specificity can be achieved, but larger studies integrating ADC and DWI data with conventional MRI are required.
We conclude that most mucinous carcinomas of the breast have a markedly higher ADC than other malignant breast tumors. The ADC and signal intensity pattern reflect the histologic characteristics of cellularity, fibrovascular tissue, and mucin-rich content. Thus, DWI is useful for evaluation of mucinous carcinoma of the breast.
Acknowledgments
We thank Peter Stanwell, physicist in the department of radiology, for
technical advice and Alba Cid and Dale Woodhams for editorial assistance.
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